Molecular genetic, biochemical, and clinical studies in three families with cardiac Fabry’s disease

The variant form of Fabry’s disease, called cardiac Fabry’s disease, which has left ventricular hypertrophy as its main clinical manifestation is not uncommon. Because there has been no pedigree analysis in families with cardiac Fabry’s disease, we performed gene analyses, enzyme assays, and cardiac evaluations in 3 distinct families with cardiac Fabry’s disease. Gene analyses were performed in all 18 members of 3 families including 3 male probands. Five hemizygotes and 6 heterozygotes were identified. Plasma α-galactosidase A activity was measured in all 18 family members. Echocardiography and electrocardiography were performed in the 5 hemizygotes and in 5 of the 6 heterozygotes. The proband and 3 heterozygotes from a pedigree with a mutation in exon 6 of the α-galactosidase A sequence leading to a Met296Ile substitution showed a decrease in α-galactosidase A activity. In a separate pedigree, a proband and his hemizygous brother, with a mutation in exon 2 leading to a Glu66Gln substitution, had a decrease in α-galactosidase A activity, whereas 3 heterozygotes had normal values. In the third pedigree, a decrease in α-galactosidase A activity was observed in 2 hemizygotes who have a mutation in exon 1 leading to an Ala20Pro substitution. Although all 5 hemizygotes exhibited left ventricular hypertrophy on echocardiography, all 5 heterozygotes lacked this finding. Because plasma α-galactosidase A activity was normal in some heterozygotes with cardiac Fabry’s disease, gene analysis is essential for an accurate diagnosis. Patients with cardiac Fabry’s disease thus show an x-linked form of hypertrophic cardiomyopathy.